Severe T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes

  1. Kerstin Renner
  2. Tobias Schwittay
  3. Sophia Chaabane
  4. Johanna Gottschling
  5. Christine Müller
  6. Charlotte Tiefenböck
  7. Jan-Niklas Salewski
  8. Frederike Winter
  9. Simone Buchtler
  10. Saidou Balam
  11. Maximilian V. Malfertheiner
  12. Matthias Lubnow
  13. Dirk Lunz
  14. Bernhard Graf
  15. Florian Hitzenbichler
  16. Frank Hanses
  17. Hendrik Poeck
  18. Marina Kreutz
  19. Evelyn Orsó
  20. Ralph Burkhardt
  21. Tanja Niedermair
  22. Christoph Brochhausen
  23. André Gessner
  24. Bernd Salzberger
  25. Matthias Mack

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Abstract

Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity.

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  1. Version published to 10.1038/s41467-021-23334-2
  2. ScreenIT

    SciScore for 10.1101/2020.09.21.20198671: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: This study was approved by the Research Ethics Committee from the University Hospital
    Consent: Informed consent was obtained from all enrolled patients (or their legal representatives) and healthy volunteers.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-CD3 (clone: OKT3) was obtained from eBiosciences (San Diego, CA) and used at 5 µg/ml.
    Anti-CD3
    suggested: None
    Where indicated a blocking anti-IL-3 antibody (10 µg/ml) was added to the samples.
    anti-IL-3
    suggested: None
    Flow cytometry: Anti-coagulated fresh blood samples (100 µl) or cells after whole blood stimulations were incubated with various panels of the following directly labeled monoclonal antibodies for 20 minutes by 4°C: anti-CD3 APC-Cy7 (clone: SK7, BioLegend)
    anti-CD3 APC-Cy7
    suggested: (BD Biosciences Cat# 557832, RRID:AB_396890)
    Samples where preincubated with 100 µg/ml mouse IgG1, kappa isotype control antibody (MOPC21, BioXCell, Lebanon, USA) for 1 hour by RT and added to the plates for 2 hours by RT (100 µl / well, diluted in PBS / 1% BSA)
    mouse IgG1
    suggested: None
    MOPC21
    suggested: None
    Software and Algorithms
    SentencesResources
    Subsequently, samples were treated with FACS Lysing Solution (BD Bioscience) for 10 min, washed with 0,9% NaCl, centrifuged, resuspended in 0,9% NaCl together with FACS counting beads (Invitrogen, Darmstadt, Germany) and acquired with a BD FACSCanto II flow cytometer and analyzed with FACSDIVA 8 software (BD Biosciences).
    FACSDIVA
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    Statistical analysis: Statistical analyses were performed using the GraphPad Prism 8 Software.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.09.21.20198671v1 on medRxiv